The present invention relates to a scaffold comprising vascularized islets which may be transplanted into the body for the treatment of diabetes.
Insulin-dependent diabetes mellitus (IDDM) is a chronic inflammatory disease in which there is autoimmune-mediated organ-specific destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. This causes glucose homeostasis abnormalities resulting in metabolic complications that are frequently debilitating and life threatening.
Replacing the beta cells has been a therapeutic goal for decades since it is believed that this treatment would prevent the morbidity and mortality associated with DM. Islet transplantation is considered a potentially curative treatment for type 1 diabetes [Shapiro A. M. Diabetes Technol Ther. 2000 Autumn; 2(3):449-52]. However, this protocol is yet to be successful. One of the most likely reasons for the poor success thus far in islet cell transplantation is that these tissue grafts must establish new vasculature from the host to survive.
Native islets in the pancreas have a rich vascular structure thought to provide efficient delivery of oxygen and nutrients to islet cells and ensure rapid dispersal of pancreatic hormones to the circulation [Jansson, L. & Carlsson, P. O. Diabetologia 45, 749-763 (2002); Menger, M. D., Yamauchi, J. & Vollmar, B. World J Surg 25, 509-515 (2001)]. In contrast, isolated islets are severed from their native vascular network. Traditionally, both in experimental and clinical islet transplantation, the islets are cultured for several days between isolation and transplantation. The endothelial cells that remain in the islets following islet isolation, the intra-islet endothelial cells, have been sparsely studied and shown to be lost following 7 days of islet culture [Mendola, J. F. et al. Transplant Proc 26, 689-691 (1994); Parr, E. L., Bowen, K. M. & Lafferty, K. J. Transplantation 30, 135-141 (1980)]. Therefore, after implantation, the survival and function of islet grafts must depend on the reestablishment of new vessels within the grafts to derive blood flow from the host vascular system [Jansson, L. & Carlsson, P. O. Diabetologia 45, 749-763 (2002); Menger, M. D., Yamauchi, J. & Vollmar, B. World J Surg 25, 509-515 (2001)]. During the time required for such revascularization, there is a much-increased susceptibility to loss from ischemic injury (e.g., lack of oxygen or nutrients). Therefore, rapid and adequate islet revascularization may be crucial for the survival and function of transplanted islets [Zhang N et al., Am J Transplant 3, 1230-1241 (2003)].
There have been attempts to improve the vascularization of transplanted pancreatic islets using acidic fibroblast growth factor. When syngeneic rat pancreas islets were transplanted into a kidney in the presence of this growth factor, the result was that more capillaries served the beta-cell-containing islet medulla, and a greater number of beta cells produced insulin [Jansson, L. & Carlsson, P. O. Diabetologia 45, 749-763 (2002); Menger, M. D., Yamauchi, J. & Vollmar, B. World J Surg 25, 509-515 (2001)].
U.S. Patent Application No. 20050048040 teaches a method for enhancing vascularization of islets by increasing the quantity and/or quality of endothelial cells residing within. U.S. Patent Application No. 20050048040 does not teach use of scaffolds to promote formation of 3D vascular structures thereby allowing ex vivo regulation of such structures.
U.S. Patent Application No. 20030113302 also teaches a method for enhancing vascularization of islets by contact thereof with endothelial cells in the presence or absence of a scaffold. U.S. Patent Application No. 20030113302 does not teach transplantation of preformed vascular beds or other vascular structures, either separately or within the scaffold.
It is estimated that less than 30% of islet mass becomes stably engrafted, despite the administration of a large quantity of islets per diabetic recipient [Boker A. et al., World J Surg 25, 481-486 (2001)]. Given a limited supply of cadaveric donors and the prevalence of type 1 diabetes, there is a widely recognized need for, and it would be highly advantageous to have, methods of preventing the loss of islet mass in the immediate post transplant period.